The subject invention is directed to certain substituted benzimidazole compounds that have improved resistance to metabolism in primates. The subject compounds are alpha adrenoceptor agonists and are useful in treating alpha agonist associated disorders.
Alpha adrenergic receptors, agonists, antagonists, and compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu and M. J. M. C. Thoolen, xe2x80x9c12.1xcex1-Adrenergic Receptorsxe2x80x9d, Comprehensive Medicinal Chemistry, Vol. 3, Membranes and Receptors, P. G. Sammes and J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. and P. A. van Zwieten, xe2x80x9cxcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters and C. J. E. Niemegeers, xe2x80x9cFurther Validation of in vivo and in vitro Pharmacological Procedures for Assessing the xcex11 and xcex12-Selectivity of Test Compounds: (2) xcex1-Adrenoceptor Agonistsxe2x80x9d, European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink and P. A. van Zwieten, xe2x80x9cQuantitative Relationships between xcex1-Adrenergic Activity and Binding Affinity of xcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans and P. A. van Zwieten, xe2x80x9cSelectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Ratxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith and M. R. Stillings, xe2x80x9cEffect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard xcex1-Adrenoreceptor Agentsxe2x80x9d, European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings and I. F. Tulloch, xe2x80x9cHeteroaromatic Analogues of the xcex12-Adrenoreceptor Partial Agonist Clonidinexe2x80x9d, J. Med. Chem., Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton and N. T. Thompson, xe2x80x9cEffects of xcex12-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Plateletsxe2x80x9d, Br. J. Pharmac., Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey and Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992.
Alpha-2 adrenergic agonists are useful for treating a variety of disorders including: respiratory disorders (e.g., asthma, nasal congestion, COPD, cough, cystic fibrosis), gastrointestinal disorders (e.g., diahrrea, irritable bowel syndrome), ocular disorders (e.g., glaucoma), cardiovascular disorders (e.g., myocardial ischemia, shock, arrhythmias, angina, congestive heart failure), benign prostatic hypertrophy and migraine. However, many compounds disclosed in the art and related in structure to those of this invention are not alpha-2 adrenoceptor selective (e.g., they interact with other alpha receptors such as alpha-1 adrenoceptors). Alpha-2 adrenoceptor selectivity is desirable when treating alpha-2 associated or alpha-2 mediated disorders. For example, alpha-2 adrenergic agonists that possess significant alpha-1 adrenergic effects are known to cause cardiovascular side effects such as hypertension. In addition, many compounds disclosed in the art and related in structure to those of this invention possess significant central nervous system (CNS) activity which may lead to undesirable side effects such as severe sedation.
It has also been observed that some alpha adrenergic agonists are subject to extensive metabolic transformation in primates. Such metabolic transformation results in inactivation of the parent compound or in the formation of an active metabolite with a different pharmacological profile from the parent compound. Of particular importance to the present invention is the metabolic transformation that occurs to some alpha adrenergic benzimidazoles that are peripherally acting alpha-2-adrenoceptor selective agonists. Metabolic N-methylation at the benzimidazole ring may result in compounds that (1) are inactive; (2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activity at other undesired receptors, such as at alpha-1 adrenoceptors; and/or (4) have an increased potential for CNS activity. Thus, there is a continuing need for peripherally acting selective alpha-2 adrenergic compounds that have lower CNS activity and that resist metabolic transformation into undesirable compounds.
The present invention is directed to compounds having a structure according to the following formula: 
wherein:
(a) R1 is alkyl;
(b) R2 is selected from the group consisting of: hydrogen, alkyl, methoxy, cyano, and halo;
(c) R3 is selected from the group consisting of: hydrogen, methyl, hydroxy, cyano and halo;
(d) R4 is selected from the group consisting of: hydrogen, methyl, ethyl and isopropyl;
(e) R5 is selected from the group consisting of: hydrogen, methyl, amino, methoxy, hydroxy, cyano and halo;
(f) provided that at least one of R2, R3, R4 or R5 is other than hydrogen or fluorine;
(g) provided that when R1 is methyl and both R2 and R5 are hydrogen, R3 is other than methyl or halo;
(h) provided that when R3 is cyano, R1 is methyl; and
any tautomer of the above structure or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide, or imide thereof.
The compounds of the present invention are useful in treating many medical disorders, including for example, respiratory disorders, ocular disorders, gastrointestinal disorders, disorders associated with sympathetic nervous system activity, migraine, peripheral pain, and disorders where vasoconstriction would provide a benefit. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment using these compounds or the compositions containing them.
xe2x80x9cAlkylxe2x80x9d is an unsubstituted saturated or unsaturated hydrocarbon chain having 1 to 3 carbon atoms. Alkyl chains may be straight, branched or cyclized. Preferred alkyl groups are methyl, ethyl, and cyclopropyl.
xe2x80x9cBiohydrolyzable amidexe2x80x9d refers to an amide of a compound of the invention that is readily converted in vivo by a subject to yield an active compound of the invention.
xe2x80x9cBiohydrolyzable esterxe2x80x9d refers to an ester of a compound of the invention that is readily converted by a subject to yield an active compound of the invention.
xe2x80x9cHaloxe2x80x9d, xe2x80x9chalogenxe2x80x9d, or xe2x80x9chalidexe2x80x9d is a chloro, bromo, fluoro or iodo. Preferred halo are chloro, bromo, and iodo. More preferred halo are chloro and bromo.
xe2x80x9cPharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987, incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
xe2x80x9cPrimatexe2x80x9d includes humans.
The present invention involves compounds having the following structure: 
In the above structure, R1 is alkyl. Preferred R1 is methyl, ethyl or cyclopropyl.
In the above structure, R2 is hydrogen, alkyl, methoxy, cyano, or halo. Preferred R2 is hydrogen, alkyl, or cyano. More preferred R2 is methyl or halo.
In the above structure, R3 is hydrogen, methyl, hydroxy, cyano or halo. Preferred R3 is cyano or hydroxy when R1 is methyl. Most preferred R3 is cyano when R1 is methyl. Preferred R3 is methyl or halo when R1 is other than methyl.
In the above structure, R4 is hydrogen, methyl, ethyl or isopropyl. Preferred R4 is hydrogen or methyl, more preferably hydrogen.
In the above structure, R5 is hydrogen, methyl, amino, methoxy, hydroxy, cyano or halo. Preferred R5 is hydrogen, methyl, or halo.
In the above structure, at least one of R2, R3, R4, and R5 is other than hydrogen or fluorine. In addition, when R1 is methyl and both R2 and R5 are hydrogen, then R3 is other than methyl or halo. Finally, when R3 is cyano, R1 is methyl.
The invention includes tautomers of the above structure. For example, when tautomer D of a molecule is shown (see below), it is understood to include tautomer E. Thus, the disclosure of one tautomeric form discloses each and all of the tautomers. 
The invention also includes pharmaceutically acceptable acid addition salts, biohydrolyzable esters, amides, and imides of the above structure.
The compounds of the invention are sufficiently basic to form acid-addition salts. The compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active. Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts. These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid""s anions.
Examples of appropriate acid-addition salts include, but at not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, mallate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfamate, and the like. However, other appropriate medicinally acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid-addition salts of the basic compounds are prepared by several methods. For example the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of the solution. Alternatively, they may be prepared by reacting the free base with an acid in an organic solvent so that the salt separates directly. Where separation of the salt is difficult, it can be precipitated with a second organic solvent, or can be obtained by concentration of the solution.
Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention. All acid-addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as an intermediate product. For example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures, these salts are clearly contemplated to be a part of this invention.
The compounds of the invention are useful for the treatment of a variety of diseases, disorders, and conditions that are modulated by alpha-2 adrenoceptors or by alpha-2 adrenoceptor activity. As used herein, the terms xe2x80x9cdisease,xe2x80x9d xe2x80x9cdisorderxe2x80x9d and xe2x80x9cconditionxe2x80x9d are used interchangeably. As used herein, a disorder described by the terms xe2x80x9cmodulated by alpha-2 adrenoceptors,xe2x80x9d or xe2x80x9cmodulated by alpha-2 adrenoceptor activityxe2x80x9d refers to a disorder, condition or disease where alpha-2 adrenoceptor activity is an effective means of alleviating the disorder or one or more of the biological manifestations of the disease or disorder; or interferes with one or more points in the biological cascade either leading to the disorder or responsible for the underlying disorder; or alleviates one or more symptoms of the disorder. Thus, disorders subject to xe2x80x9cmodulationxe2x80x9d include those for which:
The lack of alpha-2 activity is a xe2x80x9ccausexe2x80x9d of the disorder or one or more of the biological manifestations, whether the activity was altered genetically, by infection, by irritation, by internal stimulus or by some other cause;
The disease or disorder or the observable manifestation or manifestations of the disease or disorder are alleviated by alpha-2 activity. The lack of alpha-2 activity need not be causally related to the disease or disorder or the observable manifestations thereof;
Alpha-2 activity interferes with part of the biochemical or cellular cascade that results in or relates to the disease or disorder. In this respect, the alpha-2 activity alters the cascade, and thus controls the disease, condition or disorder.
The compounds of the invention are peripherally-selective alpha-2 adrenoceptor agonists. Alpha-2 adrenoceptors are distributed both inside and outside of the central nervous system. Thus, for example, a compound which displays a higher degree of central nervous system activity is preferred, but not limited to, use in central nervous system indications such as certain cardiovascular disorders (e.g., hypertension), pain, substance abuse and/or withdrawal. By centrally acting it is meant that they have some action on the alpha-2 adrenoceptors in the central nervous system in addition to their action at peripheral alpha-2 adrenoceptors.
Peripherally-acting compounds are preferred for, but not limited to, the treatment of respiratory disorders, ocular disorders, migraine, certain cardiovascular disorders, and certain gastrointestinal disorders. By peripherally acting, it is meant is that these compounds do not readily cross the blood-brain barrier and thus act primarily on alpha-2 adrenoceptors in the periphery. In addition, further specificity of action of these compounds can be achieved by delivering the agent to the region where activity is desired (for example, topical administration to the eye, nasal mucosa or respiratory tract), thereby reducing systemic exposure. Such peripherally-selective compounds have reduced CNS side effect potentials, particularly with respect to sedation. Methods are available in the art to determine which compounds are less centrally-acting than others.
The compounds of the subject invention have no or only weak alpha-1 agonist activity and have little or no effect on the central nervous system, even when dosed systemically.
Thus, the compounds of the invention are particularly useful for the treatment of respiratory disorders including nasal congestion associated with allergies, colds, and other nasal disorders, (as well as the sequelae of congestion of the mucous membranes, for example, sinusitis and otitis media), cough, chronic obstructive pulmonary disease and asthma. At effective doses, it has been found that undesired side effects can be avoided.
The compounds of the invention are also useful for the treatment of ocular disorders such as ocular hypertension, glaucoma, hyperemia, conjunctivitis, and uveitis.
The compounds of the invention are also useful for controlling gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria and peptic ulcer.
The compounds of the invention are also useful for diseases and disorders associated with sympathetic nervous system activity, including hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and benign prostatic hypertrophy.
The compounds of the invention are also useful for the prophylactic or acute treatment of migraine.
The compounds of the invention are also useful for the treatment of peripheral pain states associated with various disorders (for example, peripheral neuralgia).
The compounds of the invention are also useful for other diseases and disorders where vasoconstriction, particularly of veins, would provide a benefit, including septic or cardiogenic shock, elevated intracranial pressure, hemmorhoids, venous insufficiency, varicose veins, and menopausal flushing.
The pharmacological activity and selectivity of these compounds can be determined using published test procedures. The alpha-2 selectivity of the compounds is determined by measuring receptor binding affinities and in vitro functional potencies in a variety of tissues known to possess alpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 Adrenergic Receptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) The following in vivo assays are typically conducted in rodents or other species. Central nervous system activity is determined by measuring locomotor activity as an index of sedation. (See, e.g., Spyraki, C. and H. Fibiger, xe2x80x9cClonidine-induced Sedation in Rats: Evidence for Mediation by Postsynaptic Alpha-2 Adrenoreceptorsxe2x80x9d, Journal of Neural Transmission, Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measured using rhinomanometry as an estimate of nasal airway resistance. (See, e.g., Salem, S. and E. Clemente, xe2x80x9cA New Experimental Method for Evaluating Drugs in the Nasal Cavityxe2x80x9d, Archives of Otolaryngology, Vol. 96 (1972), pp. 524-529). Antiglaucoma activity is determined by measuring intraocular pressure. (See, e.g., Potter, D., xe2x80x9cAdrenergic Pharmacology of Aqueous Human Dynamicsxe2x80x9d, Pharmacological Reviews, Vol. 13 (1981), pp. 133-153). Antidiarrheal activity is determined by measuring the ability of the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g., Thollander, M., P. Hellstrom and T. Svensson, xe2x80x9cSuppression of Castor Oil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonistsxe2x80x9d, Alimentary Pharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy in treating irritable bowel syndrome is determined by measuring the ability of compounds to reduce the stress-induced increase in fecal output. (See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro and H. Ormsbee III, xe2x80x9cCold-restraint stress increases rat fecal pellet output and colonic transitxe2x80x9d, American Journal of Physiology, Vol. 258 (1990), pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy is determined by measuring the reduction in gastric acid secretion produced by these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca and C. Roze, xe2x80x9cEffect of xcex12-adrenoceptor agonists on gastric pepsin and acid secretion in the ratxe2x80x9d, British Journal of Pharmacology, Vol. 106 (1992), pp. 790-796). Antiasthma activity is determined by measuring the effect of the compound on bronchoconstriction associated with pulmonary challenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser and J. Hand, xe2x80x9cEffects of a Novel Leukotriene D4 Antagonist with 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, on Leukotriene-D4- and Antigen-Induced Bronchoconstriction in Guinea Pigxe2x80x9d, International Archives of Allergy and Applied Immunology, Vol. 86 (1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B. Marchette, J. Stevenson and W. Abraham, xe2x80x9cThe Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheepxe2x80x9d, American Reviews of Respiratory Disease, Vol. 130 (1984), pp. 748-754). Activity in cough is determined by measuring the number and latency of the cough response to respiratory challenges such as inhaled citric acid. (See, e.g., Callaway, J. and R. King, xe2x80x9cEffects of Inhaled xcex12-Adrenoceptor and GABAB Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigsxe2x80x9d, European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). The sympatholytic activity of these compounds is determined by measuring the reduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo and K. Starke xe2x80x9cInvolvement of peripheral presynaptic inhibition in the reduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304xe2x80x9d, European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or the reduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S. Carlsson, P. Thoren and T. Hedner, xe2x80x9cEffects of clonidine on renal sympathetic nerve -activity, natriuresis and diuresis in chronic congestive heart failure ratsxe2x80x9d, Journal of Pharmacology and Experimental Therapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis for their benefit in heart failure and benign prostatic hypertrophy. The hypotensive effect of these compounds is measured directly as a reduction in mean blood pressure (See, e.g., Timmermans, P. and P. Van Zwieten, xe2x80x9cCentral and peripheral xcex1-adrenergic effects of some imidazolidinesxe2x80x9d, European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinical studies have demonstrated the beneficial effect of alpha-2 agonists in the prevention of myocardial ischemia during surgery (See, e.g., Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg and D. Mangano, xe2x80x9cEffects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgeryxe2x80x9d, Anesthesiology, Vol. 82 (1995), pp. 620-633) and in the prevention of angina (See, e.g., Wright, R. A., P. Decroly, T. Kharkevitch and M. Oliver, xe2x80x9cExercise Tolerance in Angina is Improved by Mivazerolxe2x80x94an xcex12-Adrenoceptor Agonistxe2x80x9d, Cardiovascular Drugs and Therapy, Vol. 7 (1993), pp. 929-934). The efficacy of these compounds in cardiac reperfusion injury is demonstrated by measuring the reduction of cardiac necrosis and neutrophil infiltration (See, e.g., Weyrich, A., X. Ma, and A. Lefer, xe2x80x9cThe Role of L-Arginine in Ameliorating Reperfusion Injury After Myocardial Ischemia in the Catxe2x80x9d, Circulation, Vol. 86 (1992), pp. 279-288). The cardiac antiarrhythmic effect of these compounds is demonstrated by measuring the inhibition of ouabain induced arrhythmias (See, e.g., Thomas, G. and P. Stephen, xe2x80x9cEffects of Two Imidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and Lethality Induced by Ouabain in Guinea-Pigxe2x80x9d, Asia-Pacific Journal of Pharmacology, Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J. Martins and H. Lee, xe2x80x9cElectrophysiological effects of xcex12-adrenergic stimulation in canine cardiac Purkinje fibersxe2x80x9d, American Journal of Physiology, Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictor activity of these compounds is demonstrated by measuring the contractile properties on isolated arteries and veins in vitro (See, e.g., Flavahan, N., T. Rimele, J. Cooke and M. Vanhoutte, xe2x80x9cCharacterization of Postjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Veinxe2x80x9d, Journal of Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp. 699-705). The effectiveness of these compounds at reducing intracranial pressure is demonstrated by measurement of this property in a canine model of subarachnoid hemorrhage (See, e.g., McCormick, J., P. McCormick, J. Zabramski and R. Spetzier, xe2x80x9cIntracranial pressure reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid hemorrhagexe2x80x9d, Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibition of menopausal flushing is demonstrated by measuring the reduction of facial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H. Connor and S. Brain, xe2x80x9cThe modulation of the increase in rat facial skin blood flow observed after trigeminal ganglion stimulationxe2x80x9d, European Journal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated for alpha-2 adrenergic agonists on cutaneous blood flow in the tail (See, e.g., Redfern, W., M. MacLean, R. Clague and J. McGrath, xe2x80x9cThe role of alpha-2 adrenoceptors in the vasculature of the rat tailxe2x80x9d, British Journal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). The antimigraine effect of these compounds is demonstrated by measuring the reduction of dural neurogenic inflammation to trigeminal ganglion stimulation in the rat (See, e.g., Matsubara, T., M. Moskowitz and Z. Huang, xe2x80x9cUK-14,304, R(xe2x88x92)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanismsxe2x80x9d, European Journal of Pharmacology, Vol. 224 (1992), pp. 145-150).
It has been observed that some peripherally acting, alpha-2-selective adrenergic agonist benzimidazoles which appear metabolically stable in vitro and in vivo in rodents, are subject to metabolic transformation in primates (i.e., monkeys and humans) via N-methylation at the benzimidazole ring. Such metabolic transformation has been shown to alter the profile of these benzimidazoles such that they may be metabolized into compounds that (1) are inactive; (2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activity at other undesired receptors, such as at alpha-1 adrenoceptors; and/or (4) have an increased potential for CNS activity. The compounds of the present invention are peripherally acting selective alpha-2 adrenergic compounds that have lower CNS activity and that resist metabolic transformation into such undesirable compounds.
Metabolic stability of the compounds described above is evaluated in vitro in a precision cut liver slice assay and in vivo in pharmacokinetic studies in primates. The precision cut liver slice assay is a well recognized, validated in vitro model to study xenobiotic metabolism in animal species and humans. (See Ekins, S. xe2x80x9cPast, present, and future applications of precision-cut liver slices for in vitro xenobiotic metabolism.xe2x80x9d (Department of Medicine and Therapeutics, University of Aberdeen, UK.) Drug-Metab-Rev. (November, 1996) Vol. 28, No. 4: pp. 591-623). This assay is used to evaluate the metabolic activity of alpha-2 adrenergic agonists. The assay provides data on the biotransformations taking place within intact hepatocytes of the species of interest. Thus the full compliment of phase I and phase II metabolic enzymes are available to metabolize the drug as is the case in vivo.
For the pharmacokinetic studies, the compounds are administered orally to cynomolgus monkeys and measurements of administered benzimidazole compounds and corresponding N-methyl metabolites are made using 100 xcexcL aliquots of urine collected over various time-periods post-dose. Typically, a chemical homolog or stable-isotope-labeled internal standard is added to each sample and then diluted 100xc3x97 in water. Ten xcexcL of prepared sample is then analyzed by gradient HPLC, with tandem mass spectrometry detection. Single ion reaction monitoring schemes are employed to selectively detect the test compound, its N-methyl metabolite (if present), and the internal standard.
The compounds of the present invention show little to no metabolic N-methylation in these assays. In contrast, N-methyl metabolites were found for other alpha-2 selective benzimidazole compounds such as 5-(2-Imidazolinylamino)-4-methylbenzimidazole and 4-ethyl-5-(2-imidazolinylamino)benzimidazole. 5-(2-Imidazolinylamino)-4-methylbenzimidazole provides a very similar pharmacological profile to 7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole (see Example 1 below). That is, both compounds are very potent and selective alpha-2 adrenergic agonists, with very low CNS activity. In the precision cut liver slice assay, there is no evidence of the methyl metabolite for 7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole. However, 5-(2-imidazolinylamino)-4-methylbenzimidazole, is rapidly metabolized in this assay and it was found that its metabolite is an alpha-2 adrenergic agonist with a significantly higher potential for CNS activity than the parent compound. 4-ethyl-5-(2-imidazolinylamino)benzimidazole, another selective alpha-2 adrenergic agonist, is rapidly and extensively N-methylated in primates. Its metabolite is a very potent alpha-2 antagonist, rather than an alpha-2 agonist.
The results indicate that the metabolic transformation of benzimidazoles through N-methylation can lead to rapid formation of undesired metabolites that have different pharmacological effects relative to the parent compound and that these effects are not easily predictable. Without being bound by theory it is contemplated that the factor favorably affecting the metabolic stability of the benzimidazole compounds of this invention is the sterical hindrance provided by substituents in close proximity to the benzimidazole nitrogens.
The compounds of this invention can be made using conventional organic syntheses. Particularly preferred syntheses are carried out using the following general schemes, Schemes 1-5. In the following general reaction schemes, R1, R2, R3, R4, and R5 are as defined above. For clarity, R1, R2, R3, R4, and/or R5 do not appear on the intermediates within a specific scheme unless they are prepared or needed in that specific scheme. Preferably, R1 is part of the starting material (see Scheme 1). R2 can be part of the starting material or introduced via amination or bromination followed by functional group manipulation (see Scheme 2). R3 can be part of the starting material (see Scheme 1) or obtained by manipulation of a carboxylic acid (see Scheme 3). R4 is introduced by alkylation of an aniline substrate prior to the benzimidazole ring formation (see Scheme 1). R5 or a direct precursor to R5 is introduced during the benzimidazole ring formation (see Scheme 4). Finally, the 5-(2-imidazolinylamino) group is conveniently obtained from the aminobenzimidazoles prepared according to Schemes 1-4 (see Scheme 5).
The starting materials depicted within the schemes are commercially available or are made from commercially available starting materials and methods known to one of ordinary skill in the art. The skilled artisan may change temperature, pressure, atmosphere, solvents, or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can be readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention. 